Ethnic Variation in Inflammatory Profile in Tuberculosis

Distinct phylogenetic lineages of Mycobacterium tuberculosis (MTB) cause disease in patients of particular genetic ancestry, and elicit different patterns of cytokine and chemokine secretion when cultured with human macrophages in vitro. Circulating and antigen-stimulated concentrations of these inflammatory mediators might therefore be expected to vary significantly between tuberculosis patients of different ethnic origin. Studies to characterise such variation, and to determine whether it relates to host or bacillary factors, have not been conducted. We therefore compared circulating and antigen-stimulated concentrations of 43 inflammatory mediators and 14 haematological parameters (inflammatory profile) in 45 pulmonary tuberculosis patients of African ancestry vs. 83 patients of Eurasian ancestry in London, UK, and investigated the influence of bacillary and host genotype on these profiles. Despite having similar demographic and clinical characteristics, patients of differing ancestry exhibited distinct inflammatory profiles at presentation: those of African ancestry had lower neutrophil counts, lower serum concentrations of CCL2, CCL11 and vitamin D binding protein (DBP) but higher serum CCL5 concentrations and higher antigen-stimulated IL-1 receptor antagonist and IL-12 secretion. These differences associated with ethnic variation in host DBP genotype, but not with ethnic variation in MTB strain. Ethnic differences in inflammatory profile became more marked following initiation of antimicrobial therapy, and immunological correlates of speed of elimination of MTB from the sputum differed between patients of African vs. Eurasian ancestry. Our study demonstrates a hitherto unappreciated degree of ethnic heterogeneity in inflammatory profile in tuberculosis patients that associates primarily with ethnic variation in host, rather than bacillary, genotype. Candidate immunodiagnostics and immunological biomarkers of response to antimicrobial therapy should be derived and validated in tuberculosis patients of different ethnic origin.Author Summary: Mycobacterium tuberculosis (MTB) is the causative agent of tuberculosis. Genetically distinct strains of MTB cause disease in particular ethnic groups, and these strains vary in their ability to elicit inflammatory responses from antigen-presenting cells in vitro. Circulating and antigen-stimulated concentrations of inflammatory mediators (‘inflammatory profile’) might therefore be expected to differ between tuberculosis patients of different ethnic origin; however, this question has not previously been addressed. We therefore conducted a study to characterise ethnic variation in inflammatory profiles in a cohort of 128 newly-diagnosed tuberculosis patients in London, UK. Patients of African vs. Eurasian ancestry had distinct inflammatory profiles at presentation; differences did not relate to MTB strain variation between groups, but they did associate with ethnic variation in host genotype. Moreover, immunological correlates of the rate of MTB clearance from sputum differed between patients of African vs. Eurasian ancestry. Our findings provide insight into the mechanisms underlying ethnic variation in inflammatory profile in tuberculosis patients, and indicate that candidate immunodiagnostics and immunological biomarkers of response to tuberculosis therapy should be derived and validated in tuberculosis patients of different ethnic origin.